Method for producing prostaglandin derivative

Patent metadata

Field	Value
Publication number	US-2020239397-A1
Application number	US-202016852622-A
Country	US
Kind code	A1
Filing date	Apr 20, 2020
Priority date	Oct 31, 2017
Publication date	Jul 30, 2020
Grant date	—

Abstract

The present invention relates to a novel production method of a novel prostaglandin derivative or a pharmaceutically acceptable salt thereof useful as a medicament, and an intermediate therefor. According to the present invention, a production method of a novel prostaglandin derivative or a pharmaceutically acceptable salt thereof including a conversion step from a compound represented by the following formula 3 to a compound represented by the formula 1 can be provided:

wherein each symbol is as defined in the DESCRIPTION.

First claim

1 . A compound represented by the formula 3:

wherein, in the formula 3, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms;
R 3 is a hydroxy-protecting group;
a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration; and
Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms.

2 . A method for producing a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, comprising protecting a hydroxy group of a compound represented by the formula 3, and converting same to a compound represented by the formula 1 by subsequently removing R 3 and hydrolyzing a CO 2 Z group:

wherein, in the formula 1, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms or a substituted cycloalkyl group having 3 to 5 carbon atoms;
R 1 and R 2 are each independently a hydroxy-protecting group; and
a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration,

wherein, in the formula 3, R 3 is a hydroxy-protecting group different from R 1 and R 2 ;
Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms; and R and a methyl group bonded by a wavy line are as defined above.

3 . A method for producing a compound represented by the formula 2 or a pharmaceutically acceptable salt thereof, comprising oxidizing a hydroxy group of the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof according to claim 2 , and removing R 1 and R 2 :

wherein, in the formula 2, R and a methyl group bonded by a wavy line are as defined in claim 2 .

4 . The production method according to claim 2 , wherein the compound represented by the formula 3 is produced by reducing a carbonyl group of a compound represented by the formula 4 and 5 then removing R 4 :

wherein, in the formula 4, R 3 , R, a methyl group bonded by a wavy line and Z are as defined in claim 2 ; and R 4 is a hydroxy-protecting group different from R 3 .

5 . The production method according to claim 4 , wherein the compound represented by the formula 4 is obtained by oxidizing a hydroxy group of the compound represented by the formula 5 to convert same to the corresponding aldehyde, and reacting the compound with a compound represented by the formula 6:

wherein, in the formula 5, R 3 , R 4 , and Z are as defined in claim 4 ,

wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, and R and a methyl group bonded by a wavy line are as defined in claim 4 .

6 . The production method according to claim 5 , wherein a compound represented by the formula 5 is obtained by arylselenylating a compound represented by the formula 7 to convert same to a compound represented by the formula 8, protecting a hydroxy group, removing R 5 to convert the compound to a compound represented by the formula 9, and oxidatively eliminating an arylselenyl group to introduce a double bond:

wherein, in the formula 7, R 4 and Z are as defined in claim 5 ; and
R 5 is a hydroxy-protecting group different from R 3 and R 4 ,

wherein, in the formula 8, R 4 , R 5 and Z are as defined above; and
Ar is an aryl group or a substituted aryl group,

wherein, in the formula 9, R 3 is as defined in claim 5 ; and
R 4 , Ar and Z are as defined above.

7 . A compound represented by the formula 4.

wherein, in the formula 4, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms;
R 3 is a hydroxy-protecting group;
R 4 is a hydroxy-protecting group different from R 3 ;
a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and α-configuration; and
Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms.

8 . A method for producing a compound represented by the formula 3, comprising reducing a carbonyl group of the compound represented by the formula 4, and removing R 4 :

wherein, in the formula 3, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms;
R 3 is a hydroxy-protecting group;
a methyl group bonded by a wavy line is a methyl group having α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration; and
Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms,

wherein, in the formula 4, R 3 , R, a methyl group bonded by a wavy line, and Z are as defined above; and
R 4 is a hydroxy-protecting group different from R 3 .

9 . A method for producing a compound represented by the formula 4, comprising oxidizing a hydroxy group of a compound represented by the formula 5 to convert the compound to the corresponding aldehyde, and reacting same with a compound represented by the formula 6

wherein, in the formula 5, R 3 is a hydroxy-protecting group;
R 4 is a hydroxy-protecting group different from R 3 ; and
Z is an alkyl group having 1 to 4 carbon atoms or a substituted alkyl group having 1 to 4 carbon atoms,

wherein, in the formula 6, R′ is an alkyl group having 1 to 4 carbon atoms, R is an alkyl group having 2 to 3 carbon atoms, a substituted alkyl group having 2 to 3 carbon atoms, a cycloalkyl group having 3 to 5 carbon atoms, or a substituted cycloalkyl group having 3 to 5 carbon atoms, and a methyl group bonded by a wavy line is a methyl group having α-configuration, β-

Assignees

• Agc Inc

Inventors

• Matsumura Yasushi
• Nagai Yusuke
• Yamaguchi Yu
• Wang Lanfang

Classifications

• C07C405/00 Primary

  Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins {; Analogues or derivatives thereof} · CPC title

• C07C51/373 Primary

  by introduction of functional groups containing oxygen only in doubly bound form · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title